Toll‑Like Receptors
Toll-like receptors are pathogen-detection and clearance receptors. Toll-like receptors (TLRs) are essential regulators of innate immunity and are involved in the initiation of the inflammatory response in the event of infection. TLRs initiate a series of signaling cascades in leukocytes in response to DAMPs or pathogen-associated molecular patterns (PAMPs), resulting in enhanced cytokine production and activation (Okada & Suzuki, 2017; Tang, Kang, Coyne, Zeh & Lotze, 2012). TLR4 activation by DAMPs such as OxyHb metabolites and fibrinogen, which are produced during aneurysm rupture, has been linked to the pro-inflammatory state that follows SAH (Khey, Huard & Mahmoud, 2020). TLR4 or its related pathways were inhibited with a variety of medicines in experimental SAH, which reduced vasospasm, provided neuroprotection, and offered anti-inflammatory effects (Chang, Wu & Kwan, 2014; Liu, Yang, Pan, Liu & Ma, 2016). Fluoxetine was discovered to reduce neuroinflammation and improve neurological function in SAH rats. TLR4/MyD88/NF-κB signaling pathway is one of the probable pathways involved (Liu et al., 2018). TLR4-deficient mice had reduced infarct volumes and improved neurological and behavioral outcomes, according to a research (Caso, Pradillo, Hurtado, Lorenzo, Moro & Lizasoain, 2007). TLR4 knockout mice had lower levels of mediators linked to brain injury, including stroke-induced IRF-1, iNOS, and cyclooxygenase 2. In the brains of TLR4-deficient rats, IFN- and the lipid peroxidation marker malondialdehyde were found to be lower. After an artificial stroke, the researchers found that in TLR4-deficient rats, the matrix metalloproteinase 9 expression which helps to cause brain injury was attenuated (Caso, Pradillo, Hurtado, Lorenzo, Moro & Lizasoain, 2007). TLR4 signaling appears to control the severity of ischemia-induced neuronal damage, suggesting that TLR4 could be a target for SAH prevention and treatment (Caso, Pradillo, Hurtado, Lorenzo, Moro & Lizasoain, 2007). TREM-1 was found to be dynamically raised in the brain after eSAH, especially in microglia and vascular endothelial cells, implying that it may improve EBI through interacting with the TLR4 pathway (Sun et al., 2021).